It has long been known that over the course of an individual's life, one's tissues and organs are subjected to numerous assaults which can compromise their normal function. One of the most important attributes of tissues and organs is their ability to repair damage inflicted on it in order to maintain normal homeostasis. In many circumstances, this repair function is complete and normal function is restored without resulting sequelae. This is often the case when the insult is acute and somewhat mild in nature. However, in other cases, the attempt of a specific tissue to repair the damage inflicted results in either decreased function of the affected tissue and/or an induction of a detrimental effect on another tissue. In acute injury, the imperfect repair leading to a small decrease in tissue function may go unnoticed or be of little consequence, due to the reserve capacity of that tissue to maintain its proper function. In the case of repeated, acute injury, often seen when the injury is caused by external, environmental factors, the small incremental loss of tissue function may be additive. Thus, repeated, acute injury may result in a chronic condition and lead to ultimate failure of the affected tissue or organ. Such repeated, acute injury of various organs are seen with alcohol damage to the liver, infections of the pulmonary tract, exposure to toxins from the environment on the liver, kidney, and pulmonary tract, and the toxic effect of certain drugs, e.g., oncolytic agents, antibiotics, anti-arthritis agents, etc.
In addition to acute and repeated-acute injury, there are many conditions which can be called truly chronic. These conditions may be defined where the injury inflicted on a particular tissue or organ is continuous over a long period of time. Often, the source of chronic injury originates from a condition within the body affecting particular organs and tissues, which may or may not have been directly involved in the originating pathology. This induction of one tissue's pathology into an other tissue's function gives rise to the formation of entire syndromes of various pathologies which are often seen in chronic diseases. Imperfect or inappropriate repair attempts by affected tissues or organs in chronic pathologies may be similar to that seen with acute repair attempts or may be different; however, the results tend to be similar in that there is incremental loss of function which leads to eventual complete or partial failure.
Two examples of chronic conditions which could lead to multi-organ pathologies in which imperfect or inappropriate tissue repair is contributory to eventual organ failure are diabetes mellitus and auto immune diseases, e.g., systemic lupus erythematosus (SLE), rheumatoid arthritis, etc. Chronic pathologies may often be more insidious and less controllable in nature than some of the pathologies associated with acute injury, in that they often are undetected prior to organ failure and often result from originating insults which are poorly understood or which may result at least in part due to a genetic predisposition.
As mentioned before, many pathologies resulting from either acute or chronic insult and subsequent imperfect, ineffective, or inappropriate repair by tissues or organs, are associated with syndromes, i.e., pathologies of many different organs with multiple sequelae. Thus a single causative event can trigger a cascade of events in various body systems. For example, patients suffering from SLE may exhibit pathologies in the kidney, vasculature, lungs, and liver, largely due to one underlying cause (immune complex deposition).
The nature of the imperfect repair is diverse in different tissues and organs and not always well understood. A definition of imperfect, ineffective, or inappropriate repair of damaged tissues or organs is that repair which leads to a loss of normal function of that tissue or organ. Sometimes, this imperfect repair leads to small (focal) lesions which can be compensated by surrounding healthy tissue, thus the tissue may overall function normally in an overall sense. However, if the injuries are repeated or chronic, these incremental decreases in function inexorably lead to total failure and catastrophic results.
Some of the most common examples of imperfect repair seen in many diverse tissues and organs are an increase in fibroid deposition and a proliferation of auxiliary cells at the site of injury. Initially the injury may cause a break in a continuous, fluid carrying system such as blood vessels, arteries, nephron tubules, or air passages. The cause of this break may be mechanical or the loss of normal, interfacing cells or destruction of matrix which forms the system. Whatever the cause, the attempt by the body to repair this break often takes the form of quickly covering the break physically with a wall of cells or matrix components. This physical covering of the break, while temporarily repairing the leakage, does not restore the normal function of the system in that affected area. The repair at the site of the injury usually lacks the biological properties of the original tissue, e.g., the loss of discriminatory filtration properties in the kidney, the loss of structural integrity in arteries and vessels, a loss of permeability in the airways of the lung, etc. Microscopic examinations of these imperfect repair sites often reveal the deposition of fibrin, collagen, and other molecules which lack the biological and/or physical properties of the original matrix which it has replaced. Similarly, there is often a proliferation of auxiliary cells (sometimes referred to as connective tissue cells) which produce more non-functioning, fibroid matrix cells. Lastly, there is often a proliferation of the normal and functional cells of the particular tissue; however, the proliferation, while beneficial in number, may be ineffective in total function due to the disruption of critical architecture. Thus, the overall loss of either chemically or biologically important matrix, loss of functional cells by replacement of repair cells, or a loss of critical architecture of functioning cells leads to the failure of the tissue or organ to perform its homeostatic function.
Additionally, there are often inappropriate responses to injury and repair. Prime examples are an immune-inflammatory or inflammatory responses at the site of injury. Although these responses are beneficial and critical to protect the body from many insults such as bacteria, viruses, or external pathogens, or are beneficial in removing dead or malfunctioning cells or matrix in normal circumstances, these responses can be inappropriately triggered or become out of control at repair sites. In some cases, an inappropriate response of certain cells may be causal to further damage as well as being detrimental to the repair. For example, in auto-immune diseases, immune diseases, immune complex deposition in various tissues and organs may cause local inflammation and damage, triggering a repair response and simultaneously causing the repair to be imperfect or ineffective.
A method of inhibiting imperfect tissue repair and physiological or pathological conditions caused at least in part thereby would be beneficical.